This invention relates to a process and apparatus for para-hydrogen or ortho-deuterium induced nuclear spin polarization of an unsaturated compound, and more preferably for the preparation of a contrast agent for a magnetic resonance imaging procedure.
Hydrogen molecules (1H2) exist in two different forms, namely para-hydrogen where the nuclear spins are anti-parallel and out-of-phase (the singlet state) and ortho-hydrogen where they are parallel or anti-parallel and in-phase (the triplet state). At room temperature, the two forms are in equilibrium with an approximately 1:3 ratio of para to ortho hydrogen. At 80K the ratio is about 48:52 and at 20K it approaches 100:0 (actually about 99.8:0.2).
In contrast, deuterium (D2 or 2H2), where the 2H nucleus has a nuclear spin (S) of 1 rather than ½, exists in nine different forms, three anti-symmetric para forms and six symmetric ortho forms. At ambient temperature, the ratio of ortho-deuterium (o-D2) to para-deuterium (p-D2) in an ortho-/para-deuterium mixture is about 2:1, at 60K it is about 3:1 and at 20K it is about 98:2. (Deuterium freezes at about 19K).
In WO99/24080, which is hereby incorporated by reference, it is described how para-hydrogen may be used to catalytically hydrogenate unsaturated compounds, transferring to those compounds the anti-parallel proton spins of the para-hydrogen molecule, and transferring nuclear spin polarization from the para-hydrogen deriving protons to non-hydrogen non-zero nuclear spin (i.e. S≠0) nuclei in the hydrogenated compound, e.g. 13C or 15N nuclei. In this way, such non-zero spin nuclei may be given a nuclear spin polarization (hyperpolarization) equivalent to that achieved in a kiloTesla or higher magnetic field. The nuclear magnetic resonance signal emitted by such hyperpolarized nuclei may be used for magnetic resonance imaging in much the same way as has been done with hyperpolarized 3He-MRI.
A similar nuclear spin hyperpolarization may likewise be achieved by hydrogenation with deuterium, more particularly with o-deuterium or with hydrogen (1H2)/deuterium(2H2) mixtures, particularly deuterium or hydrogen/deuterium mixtures in which the p/o ratio for hydrogen and the o/p ratio for deuterium are higher than the equilibrium values (1:3 and 2:1) at ambient temperature, e.g. having ratios corresponding to the equilibrium values at temperatures below 80K, more particularly temperatures below 40K, especially between liquid helium (4K) temperatures and 30K, more especially at temperatures between the melting points of the hydrogen and/or deuterium and 25K.
The hydrogenation and/or deuteration, e.g. of an unsaturated bond in a substrate molecule whereby to introduce a 1H or 2H atom bound to each of the atoms linked by the unsaturated bond, serves to introduce a hydrogen/deuterium spin distribution into the hydrogenated substrate molecule which is other than the equilibrium distribution at ambient temperature. Where the substrate molecule contains non-zero nuclear spin nuclei (in natural or above natural isotopic abundances), particularly where these non-zero spin (S≠0) nuclei are close in the molecular structure of the hydrogenated substrate to the 1H or 2H atoms introduced by the hydrogenation, the introduction 1H or 2H atoms can induce a nuclear spin distribution in the S≠0 nuclei which is other than the equilibrium distribution at ambient temperature. These non-equilibrium nuclear spin distributions for the introduced protons/deuterons and for the S≠0 nuclei in the hydrogenated substrate may be harnessed to provide signal enhancement in magnetic resonance imaging (MRI) techniques, including in vivo MRI.
While WO99/24080 does describe means by which para-hydrogen hydrogenation may be effected, we have now found that hydrogenation to harness for MRI the p-H2 and/ or o-D2 induced hyperpolarization, the hydrogenation reaction is particularly favourably performed by mixing gaseous para-hydrogen and/or ortho-deuterium enriched hydrogen (i.e. where the p:o ratio of 1H2 is greater than 1:3, particularly greater than 3:7, more particularly greater than 1:1 and/or the o:p ratio of 2H2 is greater than 3:2, particularly greater than 3:1, more particularly greater than 4:1) with a spray of a solution of the unsaturated compound and a hydrogenation catalyst.